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Method of identifying a gene associated with a disease or pathological condition of the disease

a technology of pathological condition and gene, applied in the field of method of identifying a gene associated with a disease, can solve the problems of significant influence, general susceptibleness of studies to genotyping errors, etc., and achieve the effect of improving the genotype accuracy of results and separating rare variants

Active Publication Date: 2020-09-29
MACAU UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method that can accurately determine harmful and disease-causing genes. This method improves the accuracy of genotype results and helps to distinguish rare variants from common ones. This can be useful in developing diagnostic methods and treatments for diseases.

Problems solved by technology

However, WES studies are generally susceptible to genotyping errors which may significantly affect the results.

Method used

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  • Method of identifying a gene associated with a disease or pathological condition of the disease
  • Method of identifying a gene associated with a disease or pathological condition of the disease
  • Method of identifying a gene associated with a disease or pathological condition of the disease

Examples

Experimental program
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Effect test

example 1

Sample Collections

1. Patients

[0048]58 patients diagnosed as having RA were unrelated individuals of Han Chinese descent recruited from hospitals in Southern and Eastern China (Guangzhou and Changzhou) using 2010 Rheumatoid Arthritis Classification Criteria established by American College of Rheumatology and European League Against Rheumatism Collaborative Initiative (2010 ACR / EULAR).

[0049]In addition, 66 healthy and unrelated blood donors of Han Chinese ancestry from Medical Center for Physical Examination and Health Assessment, were included as controls.

[0050]Detailed descriptions of sequenced individuals and clinical characteristics of the enrolled patients are provided in Table 1 and 2. Written informed consent was obtained from all of the participants, and the study was registered in Chinese Clinical Trial Registry (ChiCTR-ROC-17010351) and approved by the local ethics committees of Macau University of Science and Technology (Macau, China).

[0051]

TABLE 1Basic information of the 1...

example 2

Preparation of a List of Candidate Genes Associated with Rheumatoid Arthritis

[0056]A list of 159 candidate RA-associated genetic variants reported by previous genome wide association studies (GWAS) with the P value threshold of P−5, as shown in Table 3, was prepared based on Rheumatoid Arthritis associated genes in the NHGRI GWAS Catalog (Welter D et al., Nucleic acids research 2014; 42:D1001-D1006) and literatures (Freudenberg J et al., Arthritis Rheumatol 2014; 66:1121-1132; Manolio T A et al., Nature 2009; 461:747-753; Okada Y et al., Nature 2014; 506:376-381; and Diogo D et al., The American Journal of Human Genetics 2013; 92:15-27).

[0057]

TABLE 3A list of candidate genes having high priority in RAGeneSNPp-ValueOdd ratioReferencesABHD6rs730815545.00E−081.18Okada Y, PMID: 24390342ACOXLrs67325653.00E−081.07Okada Y, PMID: 24390342AFF3rs9653442| 1.00E−14|1.12|1.12|Okada Y, PMID: 24390342|Stahlrs11676922| 1.00E−14|1.12E A, PMID: 20453842|Jiangrs10865035 2.00E−08|L, PMID: 24782177|Stah...

example 3

Analysis of the Whole-Exome Sequencing (WES)

[0058]To analyze the entire cohort of samples for genotype calls, variant analysis and joint genotyping were performed according to the pipeline recommended by the Genome Analysis Toolkit software and the GATK Best Practices procedures on RA patients and healthy controls (San Lucas F A et al., Bioinformatics 2012; 28:421-422; and Dong C et al., Human molecular genetics 2015; 24:2125-2137). Briefly, Burrows-Wheeler Aligner (BWA) software was utilized to align the raw sequencing reads in FASTQ formats to the 1000 Genomes (GRCh37+decoy) human genome reference. The BWA alignment files were converted to BAM files with SAMtools v1.1, which was used for sorting the BAM files. Duplicate reads were marked for BAM files with Picard MarkDuplicates (https: / / sourceforge.net / projects / picard / ). The coverage and depth were computed based on the final BAM file. Local realignment, base quality recalibration, variant calling, joint genotyping, and variant qu...

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Abstract

A method of identifying a gene associated with a disease or pathological condition of the disease includes: a) obtaining a first group of exome sequences from a first population suffering from the disease or pathological condition and a second group of exome sequences from a second population not having the disease or pathological condition; b) identifying one or more variants in the first group by comparing it with the second group, and optionally with a public database, to generate a first set of variant data; c) applying a variant quality score calibration tool with a truth sensitivity threshold to remove false-positive variants having a sensitivity lower than the threshold and background variants from the first set of variant data so as to obtain a second set of variant data; d) removing synonymous variants from the second set of variant data to obtain a third set of variant data; and e) identifying one or more deleterious variants from the third set of variant data using a gene burden analysis, optionally generating a fourth set of variant data.

Description

SEQUENCE LISTING[0001]The Sequence Listing file entitled “sequencelisting” having a size of 2,039 bytes and a creation date of 12 Jul. 2017 that was filed with the patent application is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The present application relates to a method of identifying a gene associated with a disease or its pathological condition. In particular, but not exclusively, the method makes use of exome sequences for the identification.BACKGROUND OF THE INVENTION[0003]To date, there are various methods of determining the pathogenic gene form the human genome, for example, by whole-genome sequencing. Whole-exome sequencing (WES) has become a popular means for studying the genetic information, in particular for investigating the disease related genes. However, WES studies are generally susceptible to genotyping errors which may significantly affect the results.[0004]Rheumatoid arthritis (RA) is the most common form of systemic autoimmune arthritis...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C12Q1/6883G16B50/00G16B30/00G16B20/20G16B5/00G16B15/00G16B40/20C12Q1/6869G16B30/10
CPCG16B50/00G16B30/00C12Q1/6883G16B20/20G16B5/00G16B15/00C12Q2600/156C12Q1/6869G16B40/20G16B30/10
Inventor LIU, LIANGLEUNG, LAI HANLI, YINGYAO, XIAO JUNPAN, HU DAN
Owner MACAU UNIV OF SCI & TECH
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